An estimated 182,000 new cases of invasive breast cancer occurred in the United States during 1995 and over 46,000 deaths resulted from this disease. The search for and identification of specific genetic elements which contribute to the development of breast cancer is an essential part of achieving better treatment and earlier diagnosis.
The discovery of BRCA-1 is a recent example of a burgeoning effort in molecular biology which is focused on the identification of specific disease-associated genes. BRCA-1 is the first gene discovered in an intensive worldwide search for genes associated with enhanced susceptibility to breast and ovarian cancer.
The BRCA-1 gene consists of 100 Kb of DNA which comprises 22 coding exons and encodes a protein of 1863 amino acids. (Gene Bank Accession No. U14680). Sequence analysis has provided little insight into BRCA-1 function since only a short region within the amino terminus (comprising less than 10% of the coding sequence) shows significant homology to known protein sequences. Specifically, this region consists of a putative zinc finger domain which may be critical in facilitating interactions between BRCA-1 and other proteins. Although the role this gene plays in breast cancer development is unknown, it is clear that germline mutations within this gene are associated with an 87% and 44% lifetime risk for breast cancer and ovarian cancer, respectively.
Studies suggest that mutations in BRCA-1 may play a role in nearly half the cases of familial breast cancer. However, there is little evidence indicating that this gene is involved in spontaneous (non-hereditary) breast cancer.
The present invention is the result of an effort to identify protein kinases which functionally interact with BRCA-1 in order to gain insight into BRCA-1's functional activity in regulatory pathways or other physiological processes of the cell.
Protein kinases are known to mediate cellular signals important for growth and differentiation. Typically, increased expression is associated with alterations in normal cellular processes. Some of these affected cellular processes include cell proliferation, differentiation and cancer, including, for example, breast cancer and ovarian cancer. The identification and characterization of one or more novel protein kinases should provide important insights into the mechanisms underlying oncogenesis and cellular growth control pathways. Such kinases may also be an important target for the development of chemotherapeutic agents.
There thus exists a need to identify protein kinases associated with BRCA-1 and to manipulate these protein kinases in order to diagnose or treat pathological conditions and control cellular processes. The present invention satisfies this need and provides a variety of related advantages as well.